Copyright Statement

Abstract

Background Under physiological conditions, the melanocortin
system is a crucial part of the complex network
regulating food intake and energy expenditure. In pathological
states, like cachexia, these two parameters are
deregulated, i.e., food intake is decreased and energy
expenditure is increased—a vicious combination leading
to catabolism. Agouti-related protein (AgRP), the endogenous
antagonist at the melanocortin-4 receptor (MC-4R),
was found to increase food intake and to reduce energy
expenditure. This qualifies MC-4R blockade as an attractive
mode of action for the treatment of cachexia. Based on
this rationale, a novel series of small-molecule MC-4R
antagonists was designed, from which the orally active
compound BL-6020/979 (formerly known as SNT207979)
emerged as the first promising development candidate
showing encouraging pre-clinical efficacy and safety
properties which are presented here.
Methods and results BL-6020/979 is an orally available,
selective and potent MC-4R antagonist with a drug-like
profile. It increased food intake and decreased energy
expenditure in healthy wild-type but not in MC-4R
deficient mice. More importantly, it ameliorated cachexialike
symptoms in the murine C26 adenocarcinoma model;
with an effect on body mass and body composition and on
the expression of catabolic genes. Moreover, BL-6020/979
showed antidepressant-like properties in the chronic mild
stress model in rats and exhibits a favorable safety profile.
Conclusion The properties of BL-6020/979 demonstrated
in animal models and presented here make it a promising
candidate suitable for further development towards a firstin-
class treatment option for cachexia that potentially opens
up the opportunity to treat two hallmarks of the disease, i.e.,
decreased food intake and increased energy expenditure,
with one drug.